Nrf2 promotes thyroid development and hormone synthesis.

In all vertebrates, the function of the thyroid gland is to capture iodide to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Thyroid hormone production is a multistep process that ultimately leads to the coupling of iodine to thyroglobulin, the matrix glycoprotein of hormone synthesis. This coupling is dependent on H2O2, the accumulation of which in thyroid tissue, a true iodine trap, causes a basal level of oxidative stress higher than in other tissues, which, if left unchecked, leads to cellular damage. The thyroid has efficient antioxidant and detoxifying enzymes that help it resist H202-induced oxidative stress and maintain the homeostasis necessary for hormone synthesis. By regulating the expression of genes involved in cellular detoxification processes, the transcription factor NRF2 acts as a master regulator of the cellular defense system against oxidative stress. Using zebrafish embryos and mouse thyroid organoids, we show here that direct control of thyroglobulin expression by NRF2 is an evolutionarily conserved chore mechanism in vertebrates to complete the necessary molecular defense arsenal against oxidative stress in thyroid tissue.